UOA05-22: Oral drug therapy transforms life for neonatal diabetes sufferers
Submitting InstitutionUniversity of Oxford
Unit of AssessmentBiological Sciences
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Clinical Sciences
Summary of the impact
Research undertaken by Professor Frances Ashcroft at the University of
Oxford and her collaborators at the University of Exeter has led to
several hundred neonatal diabetes (ND) patients worldwide being able to
switch from daily insulin injections to oral sulphonylurea tablet therapy
since 2008. ND is a rare but potentially devastating monogenic form of
diabetes affecting about 1 in 150,000 live births. Sufferers were
previously assumed to have type 1 diabetes and thus were treated with
insulin injections; sulphonylurea treatment has transformed their quality
of life and led to marked health improvements. It has also ameliorated the
mental and motor developmental delay that affects about a fifth of ND
Early research carried out by Professor Frances Ashcroft and colleagues
at the University of Oxford's Department of Physiology, Anatomy and
Genetics established the mechanism by which an increase in blood glucose
concentration triggers insulin secretion from the beta cells of the
pancreas. They identified the key event in this process: the closure of
ATP-sensitive potassium (KATP) channels by glucose metabolism.
They discovered that the KATP channel functions as a gated pore
and that when the pore is open insulin secretion is inhibited, and when it
is closed insulin release is stimulated.
In 1995, Ashcroft's team cloned and sequenced a key subunit of the
channel (Kir6.2) and showed the channel is made up of pore-forming Kir6.2
and regulatory SUR subunits1. This work was essential
preliminary research that enabled subsequent screening of patients' DNA
for mutations causing insulin secretory disorders. In 1997, the team
showed that ATP (produced by glucose metabolism) binds to Kir6.2 to cause
channel inhibition2 and identified mutations that impair ATP
binding. In 2003, Professor Ashcroft and Dr Declan Doyle (formerly from
the University of Oxford's Department of Biochemistry) determined the
first atomic structure of a Kir channel3. Subsequently,
Professor Ashcroft and Professor Mark Sansom, also from the Department of
Biochemistry, used this structure to produce a molecular model of Kir6.2
that enabled them to identify the ATP-binding site4. This model
explained how Kir6.2 mutations impair channel inhibition by ATP.
In 2004, Professor Andrew Hattersley of the University of Exeter found
the first mutation in Kir6.2 associated with neonatal diabetes (ND) — a
rare genetic disease that affects about 1 in 150,000 live births
worldwide, and has a serious impact on health and quality of life.
Newborns affected are smaller than those of the same gestational age, due
to lack of insulin (a growth factor) in the womb, and can fail to gain
weight normally. Diabetes develops within the first six months of life and
can be severe; some infants are admitted to hospital with diabetic
ketosis. Ashcroft's team showed that the mutation in ND impairs the
ability of ATP to shut the K ATP channel5 ; because channel closure is
required for insulin secretion, this leads to impaired insulin release and
thus to ND. Professors Ashcroft and Hattersley then suggested that it
should be possible to treat ND patients with oral sulphonylureas (already
in routine clinical use for type 2 diabetes) rather than injections of
insulin. Clinical studies showed that sulphonylureas can indeed be
successfully used to treat the diabetes of patients with this and many
other different KATP channel mutations.
Recently, Ashcroft's team made a mouse model of human ND and used this to
show that the muscle hypotonia and other motor problems of patients with
severe ND mutations originate in the brain, not the muscle. This has
implications for therapy, as drugs must cross the blood-brain barrier6.
Ongoing studies of mice models reveal that sulphonylurea therapy preserves
beta cell function and mass better than insulin, and start to explain some
of the differences in phenotype between ND and type 2 diabetes.
References to the research
1. Sakura H, Ämmälä C, Smith PA, Gribble FM, Ashcroft FM. (1995) Cloning
and functional expression of the cDNA encoding a novel ATP-sensitive
potassium channel subunit expressed in pancreatic β-cells, brain, heart
and skeletal muscle. FEBS Letters 377: 338-344. doi:
10.1016/0014-5793(95)01369-5 Paper describing the cloning of
Kir6.2. The research also established that the Kir6.2 and SUR subunits
compose the KATP channel.
2. Tucker SJ, Gribble FM, Zhao C, Trapp S, Ashcroft FM. (1997) Truncation
of Kir6.2 produces ATP-sensitive K+ channels in the absence of
the sulphonylurea receptor. Nature 387: 179-183. doi: 10.1038/387179a0 Paper
reporting that the site at which ATP acts to inhibit the KATP
channel is located on Kir6.2, and that SUR1 is required for
sensitivity to sulphonylureas.
3. Kuo A, Gulbis JM, Antcliff JF, Rahman T, Lowe ED, Zimmer J,
Cuthbertson J, Ashcroft FM, Ezaki T, Doyle DA. (2003) Crystal structure of
the potassium channel KirBac1.1 in the closed state. Science 300:
1922-1926. doi: 10.1126/science.1085028 Paper reporting the
structure of a Kir potassium channel, including identification of
structural elements involved in gating.
4. Gloyn AL, Pearson ER, Antcliff JF, Proks P, Bruining J, Slingerland
AS, Howard N, Srinivasan S, Silva JMCL, Molnes J, Edghill EL, Frayling TM,
Temple IK, Mackay D, Shield JPH, Sumnik Z, van Rhijn A, Wales JKH, Clark
P, Gorman S, Aisenberg J, Ellard S, Njølstad PR, Ashcroft FM, Hattersley
AT. (2004) Activating mutations in the gene encoding the ATP-sensitive
potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New
England Journal Medicine 350: 1838-1849. doi: 10.1056/NEJMoa032922 First
report of activating Kir6.2 mutations that cause neonatal diabetes.
All functional studies and molecular modelling were done by the
Ashcroft team, and the genetic studies were done by the Hattersley
5. Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM.
(2004) Molecular basis of Kir6.2 mutations associated with neonatal
diabetes or neonatal diabetes plus neurological features. Proc Natl Acad
Sci U S A. 101: 17539-17544. doi: 10.1073/pnas.0404756101 Paper
elucidating the molecular mechanism of action of Kir6.2 mutations
causing ND. Ashcroft designed and conducted the experiments and wrote
the paper; the Hattersley team identified the mutations.
6. Clark RH, McTaggart JS, Webster R, Mannikko R, Iberl M, Sim XL,
Rorsman P, Glitsch M, Beeson D, Ashcroft FM. (2010) Muscle dysfunction
caused by a KATP channel mutation in neonatal diabetes is
neuronal in origin. Science 329: 458-461. doi: 10.1126/science.1186146 Paper
reporting that the motor impairments of ND originate in the central
nervous system rather than in muscle or peripheral nerves.
Funding for research:
This work has been continuously supported by the Wellcome Trust and the
Royal Society, with grants in excess of £10.5M since 1999.
Details of the impact
The work of Ashcroft at Oxford, with Hattersley's team at Exeter, has
transformed therapy for people born with ND. Until 2006, ND patients were
treated with insulin because their clinical characteristics suggested an
unusually early onset form of type 1 diabetes (in which insulin-secreting
beta cells are destroyed and exogenous insulin is essential). As a direct
result of the research described above, the first patient was switched to
oral sulphonylurea treatment in August 2006, and since then at least 500
patients have transferred from insulin injections to the oral drugs, the
bulk of them from 2008 onwards. Clinicians worldwide now routinely screen
infants presenting with ND, as well as adult patients who developed
diabetes at a young age, for KATP channel mutations.
Transfer to oral drugs has not only transformed the quality of life for
those with ND (and that of their families), it has also had marked
clinical benefits. Fluctuations in blood glucose, a common problem in ND
patients, are substantially reduced, and potentially dangerous
hypoglycaemic episodes are less common. Blood glucose control is
substantially improved, lowering the risk of diabetic complications, such
as blindness, kidney disease, heart disease and limb amputations. Such
complications account for the majority of the morbidity and mortality
burden of diabetes, so this reduction results in life-time cost savings of
eventual healthcare needs. Furthermore, daily insulin injections are
inconvenient, unpleasant, restrictive in terms of lifestyle, and
relatively expensive. By contrast, sulphonylureas are cheap, off-patent,
drugs that have been in routine clinical use for treating type 2 diabetes
for more than 30 years. In the first study into the use of sulphonylureas
to treat ND, 90% of the trial group successfully discontinued insulin
after receiving sulphonylureas7.
About 20% of ND patients with K ATP channel mutations also have
neurological symptoms8, 9. Some have severe mental and motor
developmental delay and (in approximately 3% of cases) epilepsy in
addition to ND (named DEND syndrome by Ashcroft and Hattersley)8.
Most also have muscle hypotonia accompanied by delayed speech and walking.
These symptoms arise because KATP channels are found in brain
and muscle, as well as in pancreatic beta cells. Sulphonylurea drugs
ameliorate the neurological problems in some of these patients8.
Importantly, some children who were started on sulphonylureas at diagnosis
have not yet developed obvious neurological complications, although it is
too early to be certain if this will be true for all patients.
Since 2008, sulphonylurea therapy has become the therapy of choice for
patients with KATP channel mutations. Guidelines from the
International Society for Pediatric and Adolescent Diabetes state that ND
patients should be treated with sulphonylurea drugs10. The NHS
has also approved research showing that genetic testing for ND is cost
effective, since transfer to sulphonylurea drugs leads to significant cost
savings in the long term11. Ashcroft and Hattersley have
disseminated the results of their research in seminars, lectures, media
interviews and other venues, which has been vital in reaching the greatest
number of clinicians and new families who might benefit from the drug
treatment; as a direct result there are now clinics worldwide offering
genetic testing for ND.
Ashcroft and Hattersley organised and ran the first `Families Day'
meeting for patients with ND and their families in July 2009 in London.
Several families remain in regular contact with one or both of the Oxford
and Exeter teams. Through such contacts it has become apparent that apart
from the clinical benefits associated with sulphonylurea therapy, the
impact upon an individual's quality of life, and that of their family, has
been considerable. One patient described switching from insulin therapy to
sulphonylureas as `like night and day'12, and another said the
new treatment had `given him his life back'13. Numerous other
patient stories describe ways that sulphonylurea treatment has
revolutionised their lives with diabetes14-16; one mother
reports that thanks to sulphonylurea treatment her daughter `has now been
completely off insulin for seven years with the blood sugar control of a
non-diabetic. A truly life-changing miracle'17. The impact of
this research has resulted from an extremely effective collaborative
interaction between the researchers at Oxford and Exeter, clinicians,
patients, and their families.
Sources to corroborate the impact
- Pearson ER, Flechtner I, Njølstad PR, Malecki MT, Flanagan SE, Larkin
B, Ashcroft FM, Klimes I, Codner E, Iotova V, Slingerland AS, Shield J,
Robert J, Holst JJ, Clark PM, Ellard S, Søvik O, Polak M, Hattersley AT.
(2006) Switching from insulin to oral sulfonylureas in patients with
diabetes due to Kir6.2 mutations. New England Journal Medicine 355:
467-477. doi: 10.1056/NEJMoa061759 Paper reporting the successful
transfer of ND patients from insulin to sulphonylureas, and also
showing that improved glycaemic control was sustained.
- Mlynarski W, Tarasov T, Gach A, Girard CA, Pietrzak I, Zubcevic L,
Kusmierek J, Klupa T, Malecki MT, Ashcroft FM. (2007) Sulfonylurea
improves CNS function in a case of intermediate DEND syndrome caused by
a mutation in KCNJ11. Nature Clinical Practice Neurology 3: 640-645.
doi: 10.1038/ncpneuro0640 Paper reporting improved glucose
homeostasis and mental and motor function in a patient with both ND
and neurological symptoms.
- Shimomura K, Hörster F, de Wet H, Flanagan SE, Ellard S, Hattersley
AT, Wolf NI, Ashcroft FM, Ebinger F. (2007) A novel mutation causing
DEND syndrome — a treatable channelopathy of pancreas and brain.
Neurology 69: 1342-1349. doi: 10.1212/01.wnl.0000268488.51776.53 Paper
reporting that sulphonylurea treatment improved both psychomotor
abilities and epilepsy in a child with ND.
- Hattersley A, Bruining J, Shield J, Njølstad P, Donaghue KC. (2009)
The diagnosis and management of monogenic diabetes in children and
adolescents. Pediatric Diabetes 10(S12): 33-42. doi:
10.1111/j.1399-5448.2009.00571.x Guidelines from the
International Society for Pediatric and Adolescent Diabetes for the
treatment of ND, recommending sulphonylurea.
- Greeley SAW, John PM, Winn AN, Ornelas J, Lipton RB, Philipson LH,
Bell GI, Huang ES. (2011) The cost-effectiveness of personalized genetic
medicine: the case of genetic testing in neonatal diabetes. Diabetes
Care 34: 622-627. doi: 10.2337/dc10-1616 NHS Economic Evaluation
database entry giving an objective evaluation of a study showing
that genetic testing of patients with ND leads to significant cost
- Wellcome Trust. Breaking Through Neonatal Diabetes (HD) [online
video]. London: Wellcome Trust; 23 Jul 2009. Available from:
Building on the ND `Families Day' in July 2009, a video was
produced by the Wellcome Trust that features ND patients discussing
the way sulphonylurea treatment has changed their lives.
- Elliott J. `They have given me my life back'. BBC News. 31 Aug 2009
Health. Available from:
BBC report on the major positive impact sulphonylurea treatment
has had on a patient, together with an account of `ND Families Day'.
- BBC Radio 4. Frances Ashcroft: The Life Scientific, London; 15 May
2012. Available from:
Parent's testimony on `The Life Scientific', a BBC Radio interview
with Professor Ashcroft, confirming the benefits of sulphonylurea
treatment (at 20 minutes 27 seconds).
- University of Chicago Gleacher Center. Celebrating the Miracles
[online video]. Chicago: 4 Oct 2010. Available from: http://youtu.be/OglCARmrAPE
A film made by a parent, featuring many others, discussing how
medical breakthroughs such as sulphonylurea treatments have changed
their lives and their families' lives for the better.
- Journey to a Miracle: Freedom from Insulin — Pilot for USA television
documentary in production 2013. Available from: http://tmktv.com/result.php?title=Journey-to-a-Miracle:-Freedom-from-
Insulin---Pilot A PBS documentary outlining the impact of
switching patients from insulin injections to oral therapies for
neonatal diabetes with patient and family testimonials.
- Email letter from the mother of a patient (held on file) outlining
the impact of the oral therapy on the health and wellbeing of her